The identification of tissue type based upon responses to incident light and/or electrical stimulation is well known. This has led to diagnostic techniques and apparatus for identifying tissue types such as cancerous or pre-cancerous. Existing techniques for identifying cancers run the gamut from microscopic examination of tissue smears by trained cell pathologists, to the study of the fluorescence, electrical and other physical properties of tissues. Much research has been devoted to the identification and comparison of optical and electrical characteristics of healthy and damaged tissue in the hope that it could lead to new diagnostic techniques. The research is driven by the fact that none of the present methods for the detection of cervical cancers are sufficiently accurate, and the risks of incorrect diagnosis are severe. Many cancerous conditions, especially cervical cancers, are treatable by removal of the involved area if caught in time, but become deadly if not.
The Papanicolaou ("Pap") smear has been the method of choice for cervical screening for over 50 years. The sensitivity limitations of the Pap smear have been well documented, and include an overall false negative rate variously reported as between 20-40%, and between 6-55%. False negative rates for pre-cancerous lesions have been assessed as 28%, and between 20-50%. In addition, the estimated specificity for the test has been profoundly affected by the widespread introduction in the USA of the Bethesda cytology classification system. The system, introduced in 1989 and revised in 1991, introduced a new cytologic category, Atypical Squamous Cells of Undetermined Significance (ASCUS). It has been noted that "ASCUS is not a morphologic entity, but rather an `I don't know` category"; "ASCCP Practice Guideline: Management guidelines for follow-up of Atypical Squamous Cells of Undetermined Significance (ASCUS)", The Colposcopist 1996: XXVII(1), 1-12. Other equivalent cytological categories including morphologic changes bordering on mild dyskaryosis, atypical cells, minor atypia and minimal atypia also represent a high false positive rate if all women with screening results in these categories are referred for diagnostic examination.
Most research has focused on isolated techniques, either optical (reflecting or scattering light or infra-red radiation from tissue), or electrical (studying the conductivity of tissue at different depths below the surface), or otherwise responding to such things as magnetic fields or pressure. Fricke and Morse, in 1926, conducted a study involving the electrical measurement of breast tumors; Fricke H and Morse S, "The electric capacity of tumors of the breast". J Cancer Res 1926: 10, 340-76. This was followed in 1949 with a study of electrical parameters derived from measurements of cervical tissue by Langman and Burr who found "significant differences in cancerous and non-cancerous tissue". Langman L J and Burr H S, "A technique to aid in the detection of malignancy of the female genital tract", Am J. Obstet Gynecol 1949: 57, 274-81. Researchers have measured various physical properties of tissue samples for many years, many having concentrated on bulk properties of tissue rather than concentrating on the epithelial layers. Very few groups have been successful in a transition to in vivo studies. Some examples of work which specifically focused on examination of epithelial tissue are as follows:
The impedance of single layers of cultured cells grown across electrodes has been used to assess their growth and physiological activity under various circumstances. Hyun, C. H., et al., "Morphological Factors Influencing Transepithelial Conductance in a Rabbit Model of Ileitis," Gastroenterology, 1995; 109:13-23. Epithelium has been removed from the body, prepared and placed in experimental apparatus for detailed measurement of its electrical properties. Kottra, G. et al., "Rapid Determination of Intraepithelial Resistance Barriers by Alternating Current Spectroscopy," Pflugers Archiv: European Journal of Physiology, 1984; 402:409-420. Electrical impedance tomography has been used to develop a technique for imaging deeper structures in the body by mapping impedance measurements across the surface of the skin. This technique tries to deliberately eliminate the effect of the surface epithelium. Webster, J. G., Electrical Impedance Tomoaraphy, Bristol & New York: IOC Publishing, 1990. The use of the scattering of light to characterize tissue is known. Bigio, I. J. et al., "Optical Diagnostics Based on Elastic Scattering: An Update of Clinical Demonstrations with the Optical Biopsy System", SPIE 2324:46-54, 1994. Representative patents are U.S. Pat. No. 4,407,300, "Potentiometric diagnosis of cancer in vivo"; U.S. Pat. No. 5,353,802, "Device for measurement of electrical impedance of organic and biological materials"; U.S. Pat. No. 5,439,000, "Method of diagnosing tissue with guide-wire"; and U.S. Pat. No. 5,560,357, "D.C. epidermal biopotential sensing electrode assembly and apparatus for use therewith". Representative publications are: Avis, N. J. et al. (post 1995) "In-vitro multifrequency electrical impedance measurements and modeling of the cervix in late pregnancy"; Marino, A. A. et al.(Undated Abstract), "On the relationship between surface electrical potentials and cancer"; Melczer (1977), "Electrical potentials in epithelial neoplasms", British Jour. of Dermatology 96, 572; and Thornton (1991), "Relaxation distribution function of intracellular dielectric zones as an indicator of tumorous transition of living cells", IMA Jour. of Math. Applied in Med. & Bio. 8, pp. 95-106.
U.S. Pat. Nos. 5,042,494 and 5,348,018 are typical of those that concern the examination of tissue absorption, fluorescence and autofluorescence applied to melanomas and other tissue types. These techniques are further discussed in Van Gemert, M. J. C. et al., "Skin Optics". IEEE Transactions on Biomedical Engineering 36(12):1146-1154, 1989; and Tuchin, V. V., (ed.), Selected Papers on Tissue Optics--Applications in Medical Diagnostics and Therapy, SPIE Milestone Series, Volume MS 102. Representative patents are: U.S. Pat. No. 4,213,462, "Optical assembly for detecting an abnormality of an organ or tissue and method"; U.S. Pat. No. 4,930,516, "Method for detecting cancerous tissue using visible native luminescence"; U.S. Pat. No. 5,036,853, "Use of light conveyed by fiber optics to locate tumors. Physiological probe"; U.S. Pat. No. 5,042,494, "Method and apparatus for detecting cancerous tissue using luminescence excitation spectra"; U.S. Pat. No. 5,131,398, "Method and apparatus for distinguishing cancerous tissue from benign tumor tissue, benign tissue or normal tissue using native fluorescence"; U.S. Pat. No. 5,179,938, "Apparatus for endoscopic examination of body cavity using chemiluminescent light source"; U.S. Pat. No. 5,348,018, "Use of fluorescence or luminescence. Method for determining if tissue is malignant as opposed to non-malignant using time-resolved fluorescence spectroscopy"; and U.S. Pat. No. 5,413,108, "Method and apparatus for mapping a tissue sample for and distinguishing different regions thereof based on luminescence measurements of cancer-indicative native fluorophor". Representative publications are: Bigio et al. "Non-invasive identification of bladder cancer with sub-surface backscattered light." SPIE Symp. on Biomed. Optics, Jan. 2-28, 1994; Bigio, et al. "Optical diagnostics based on elastic scattering: recent clinical demonstrations with the Los Alamos Optical Biopsy System" SPIE Vol. 2081 Optical Biopsy (1993); Coppleson, M., et al. "An electronic approach to the detection of pre-cancer and cancer of the uterine cervix: a preliminary evaluation of Polarprobe" Int'l Gynecol Cancer 1994, 4, 79-83; Coppelson et al. 1991 Prototype Cervix Probe. Abstract in Int. J. Gynecol. Obstet. XIII World Congress Of Gynecology and Obstetrics; and Wagnieres, G. et al. (1990) "Photodetection of early cancer by laser induced fluorescence of tumor-selective dye: apparatus design and realization". SPIE Vol. 1203 Photodynamic Therapy Mechanisms II.
The background technology of the present invention has been described in Wunderman et al., "A precancer detection instrument," J. Gynecol Tech. 1995: 1(2), 105-9 and Thompson R L et al., "A non-invasive probe for cervical cancer detection", Proceedings IE Aust. Electrical Engineering Congress 1994.